Stroke and traumatic brain injury are major causes of morbidity and disability and functional recovery is slow and uncertain. Our preliminary data demonstrate that intravenously transplanted bone marrow stromal cells (MSCs) migrate to the stroked and injured brain tissue and improve functional recovery, This application is concerned with elucidating the cellular and molecular mechanisms responsible for the beneficial effect of MSC therapy on stroke and traumatic brain injury. The major hypothesis to be tested is that the MSCs delivered to the brain after stroke and traumatic brain injury enhance angiogenesis, promote axonal and dendritic sprouting and synapse formation, reduce cell death in the boundary regions of injured brain, and promote neurogenesis in the subventricular zone and dentate gyrus and thereby reduce neurological deficits, in addition, we propose to test the hypothesis that therapeutic benefit derives from MSC-induced increase in brain of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and brain-derived neurotrophic factor (BDNF). This hypothesis will be tested by blocking receptors and using gone knock-out mice. Specifically, by blocking VEGF receptor 2, we will examine the effect of VEGF on MSC-enhanced angiogenesis. Using bFGF-/- and BDNF-/-mice, we will examine the effects of bFGF and BDNF on MSC-induced axonal and dendritic sprouting and synapse formation and neurogenesis. Angiogenesis, neurogenesis and axonal and dendritic sprouting and synapse formation will be measured using Laser Scanning Confocal Microscopy, and a novel software program for three dimensional image analysis. We believe that these are unique and fresh approaches that may provide fundamental insights into the cellular and molecular mechanisms underlying the therapeutic benefit provided by MSC cellular therapy of stroke and traumatic brain injury.